Mutations in any of three genes, HEXA, HEXB and GM2A, result in forms of the GM2 gangliosidoses, a group of severe neurodegenerative diseases. We are in the process of creating models of these genetic disorders through targeted gene disruption in the mouse. HEXA- We have produced mice with biochemical and neuropathologic features of Tay-Sachs disease by disruption of the Hexa gene encoding the alpha subunit of beta-hexosaminidase A. The mutant mice displayed less than 1% of normal beta-hexosaminidase A (beta-hex A) activity and accumulated GM2 ganglioside in brain in an age-dependent manner. The accumulated ganglioside was stored in neurons as membranous cytoplasmic bodies characteristically found in the neurons of Tay-Sachs disease patients. HEXB - The Hexb gene encoding the beta subunit of beta-hex A has been disrupted in embryonic stem cells and chimeric mice have been derived. When the homologous gene is defective in humans, Sandhoff disease results. GM2A - The GM2 activator protein forms a substrate-complex with GM2 ganglioside which enables degradation of the ganglioside by beta-hex A. Mutations in the human GM2 activator protein gene result in the GM2 gangliosidosis AB variant. We have isolated and sequenced a full-length mouse GM2 activator protein cDNA. The Gm2a gene was mapped to a region on mouse Chromosome 11 that is homologous with a segment of human chromosome 5 containing the orthologous human gene. In addition, a Gm2a related sequence (Gm2a-rsl) was mapped to mouse Chromosome 5.